Recent remarkable advances in understanding the cellular and molecular mechanisms of wound repair have not yet led to similar advancements in wound care. An effective wound repair-promoting drug or composition would find multiple applications including healing of surgical wounds, accidental (burnt or cut) wounds, sunburns, or wounds generated by cosmetic surgeries. In addition, such agent(s) would also be expected to increase the efficacy of various skin grafting procedures as well as help to reduce skin damage induced by aging or environmental stresses.
Wound repair involves three major partially overlapping complex processes that follow a specific time sequence: inflammation, tissue formation, and tissue remodeling [Martin, P. (1997) Wound healing—Aiming for perfect skin regeneration. Science 276, 75-81]. These events are regulated by numerous growth factors and cytokines [Werner S. and Grose, R. (2003) Regulation of wound healing by growth factors and cytokines. Physiol. Rev. 10, 835-870]. Because of the complexity of these processes, application of a single growth factor does not seem to be sufficient to significantly promote wound healing. For example, platelet-derived growth factor (sold under the name of “Regenerex”) was approved by FDA for wound healing application, but proved relatively ineffective. A probable reason for this is that platelet-derived growth factor stimulates only the proliferation of fibroblasts in the deeper dermis layer, and this may not be sufficient to significantly impact the proliferation of cells in the epidermis (keratinocytes).
Application of a mixture of growth factors would be another possibility to promote wound healing. However, most growth factors are short lived (rapidly degraded by proteases present in the wound fluid) and often counteract each other's effects or may be difficult to establish an optimal dose. For example, transforming growth factor-α and transforming growth factor-β have stimulatory and inhibitory effects on keratinocyte proliferation, respectively [Werner S. and Grose, R. (2003) Regulation of wound healing by growth factors and cytokines. Physiol. Rev. 10, 835-870]. High-dose epidermal growth factor induces the production of transforming growth factor-β and thereby inhibits proliferation of keratinocytes [Yamasaki, K., Toriu, N., Hanakawa, Y., Shirakata, Y., Sayama, K., Takayanagi, A., Ohtsubo, M., Gamou, S., Shimizu, N., Fujii, M., Miyazono, K, and Hashimoto, K. (2003) Keratinocyte growth inhibition by high-dose epidermal growth factor is mediated by transforming growth factor β autoinduction: A negative feedback mechanism for keratinocyte growth. J. Invest. Dermatol. 120, 1030-1037]. Thus, it is difficult to establish an effective dose for epidermal growth factor. For these and other reasons, development of an effective growth factor mixture to promote wound healing has, so far, met with only limited success. In conclusion, there is still an unmet need to provide an agent or a mixture of agents that effectively promote(s) wound repair and restore(s) or maintain(s) the healthy structure of skin challenged by environmental stresses.